We have been exploring the potential antiviral efficacy of nucleoside analogues for treatment of chronic hepatitis B virus infection. Initially we explored the drug FIAC for inhibition of CMV infection in AIDS patients. Antiviral activity was not seen at tolerated doses and studies turned to the drug's metabolic derivative, FIAU. Studies showed intolerance at high doses but excellent tolerance and profound inhibitory activity at lower doses against hepatitis B virus (HBV). The initial studies involved HIV positive patients with co-existing chronic HBV infection. Profound and even permanent reductions in circulating HBV DNA and antigens were achieved with oral FIAU at daily doses of 0.1, -.5, or 1 mg/kg for 14 days. We then turned to a broader dose modification study in normal patients with chronic HBV infection. Studies compared antiviral efficacy at .05, 0.1, 0.25 and 0.5 mg/kg per day for 28 days. We noted profound inhibition of HBV infection even at the lowest doses and in the absence of any substantial side effects. By 9 months after treatment 9 of 24 patients had lost HBV DNA; 2 of which lost HBeAg. Based on these findings additional HIV-negative chronic HBV patients were enrolled in a randomized study comparing 0.1 and 0.25 mg/kg per day for 6 months to determine long term safety and efficacy. The trial was terminated 6/26/93 because of the emergence of life-threatening toxicity in the study. The past year of work included long term follow up of the study patients and a continuing exploration of the cellular and biochemical bases for the toxicity. We also began studies of additional, newer nucleoside analogs that already have considerable evidence of safety in other disease settings. We obtained an IND to study famciclovir in combination with recombinant interferon. Patients with chronic hepatitis B who have failed interferon or are unlikely to respond to interferon are being enrolled. Other studies involving lamivudine are being explored, depending on the efficacy of the combined famciclovir and interferon treatment.